Short-term hypoxia triggers ROS and SAFB mediated nuclear matrix and mRNA splicing remodeling

Taze, Chrysa; Drakouli, Sotiria; Samiotaki, Martina; Panayotou, George; Simos, George; Georgatsou, Eleni; Mylonis, Ilias

doi:10.1016/j.redox.2022.102545

Cited by 7 publications

(6 citation statements)

References 61 publications

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“…SAFB proteins have been known for more than three decades and found to be involved in a large variety of nucleic acid-related biological functions [ 16 ], specifically in the context of stress response. Their supposedly dual nucleic acid-binding potential has made them bona fide anchoring proteins to locate and regulate DNA- and RNA-processing events, best represented by SAFB2 [ 23 , 58 ]. How exactly this is organized through SAFBs as integrators of RNA, DNA and protein binding has majorly remained elusive, while atom-resolved pictures would yield valuable insights into the respective functions.…”

Section: Discussionmentioning

confidence: 99%

“…The latter would yet more put into focus the question of SAFB2 simultaneously interacting with DNA and RNA. In general, such interchanging or mixed D/RNPs including SAFBs could couple the events of specific local chromatin remodeling, transcriptional regulation of miR genes and the subsequent processing of nascent transcripts, or, as shown very recently in an example, for the interplay of nuclear matrix remodeling and mRNA splicing regulation [ 58 ] by SAFB2. In this regard, a close proximity of both bindings might be favored and give rise to a functional switch, in that internal protein interactions are crucial for the formation of correct D/RNPs.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, binding of SAFBs has very recently been brought in correlation with the nuclear localization of linear, mostly unspliced RNAs [ 77 ], indicating an anchoring role for them in transcript processing, which is susceptible to stress in a reversible manner [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

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Insight into the Structural Basis for Dual Nucleic Acid—Recognition by the Scaffold Attachment Factor B2 Protein

Korn

Ehr

Dhamotharan

et al. 2023

IJMS

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The family of scaffold attachment factor B (SAFB) proteins comprises three members and was first identified as binders of the nuclear matrix/scaffold. Over the past two decades, SAFBs were shown to act in DNA repair, mRNA/(l)ncRNA processing and as part of protein complexes with chromatin-modifying enzymes. SAFB proteins are approximately 100 kDa-sized dual nucleic acid-binding proteins with dedicated domains in an otherwise largely unstructured context, but whether and how they discriminate DNA and RNA binding has remained enigmatic. We here provide the SAFB2 DNA- and RNA-binding SAP and RRM domains in their functional boundaries and use solution NMR spectroscopy to ascribe DNA- and RNA-binding functions. We give insight into their target nucleic acid preferences and map the interfaces with respective nucleic acids on sparse data-derived SAP and RRM domain structures. Further, we provide evidence that the SAP domain exhibits intra-domain dynamics and a potential tendency to dimerize, which may expand its specifically targeted DNA sequence range. Our data provide a first molecular basis of and a starting point towards deciphering DNA- and RNA-binding functions of SAFB2 on the molecular level and serve a basis for understanding its localization to specific regions of chromatin and its involvement in the processing of specific RNA species.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Insight into the Structural Basis for Dual Nucleic Acid—Recognition by the Scaffold Attachment Factor B2 Protein

Korn

Ehr

Dhamotharan

et al. 2023

IJMS

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show abstract

“…SAFB proteins are known for more than three decades and found involved in a large variety of nucleic acid-related biological functions [16], specifically in the context of stress response. Their supposedly dual nucleic acid-binding potential has made them bona fide anchoring proteins to locate and regulate DNA- and RNA-processing events, best represented by SAFB2 [23,58]. How exactly this is organized through SAFBs as integrators of RNA-, DNA- and protein-binding has majorly remained elusive, while atom-resolved pictures would yield valuable insights into the respective functions.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, binding of SAFBs has very recently been brought in correlation with the nuclear localization of linear, mostly unspliced RNAs [74] indicating an anchoring role for them in transcript processing, which is susceptible to stress in a reversible manner [58].…”

Section: Discussionmentioning

confidence: 99%

Insight into the structural basis for dual nucleic acid - recognition by the Scaffold Attachment Factor B2 protein

Korn

Ehr

Dhamotharan

et al. 2022

Preprint

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The family of scaffold attachment factor B (SAFB) proteins comprises three members and was first identified as binders of the nuclear matrix/scaffold. Over the past two decades, SAFBs were shown to act in DNA repair, mRNA/(l)ncRNA processing, and as part of protein complexes with chromatin-modifying enzymes. SAFB proteins are approximately-100-kDa-sized dual nucleic acid-binding proteins with dedicated domains in an otherwise largely unstructured context, but whether and how they discriminate DNA- and RNA-binding has remained enigmatic. We here provide the SAFB2 DNA- and RNA-binding SAP and RRM domains in their functional boundaries and use solution NMR spectroscopy to ascribe DNA- and RNA-binding functions. We give insight into their target nucleic acid preferences and map the interfaces with respective nucleic acids on sparse data-derived SAP and RRM domain structures. Further, we provide evidence that the SAP domain exhibits intra-domain dynamics and a potential tendency to dimerise, which may expand its specifically targeted DNA sequence range. Our data provide a first molecular basis of and a starting point towards deciphering DNA- and RNA-binding functions of SAFB2 on the molecular level and serve a basis for understanding its localization to specific regions of chromatin and its involvement in the processing of specific RNA species.

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Autophagy‐dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival

Kerry,

Specker,

Mizzoni

et al. 2024

FEBS Letters

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Cells remodel splicing and translation machineries to mount specialized gene expression responses to stress. Here, we show that hypoxic human cells in 2D and 3D culture models increase the relative abundance of a longer mRNA variant of ribosomal protein S24 (RPS24L) compared to a shorter mRNA variant (RPS24S) by favoring the inclusion of a 22 bp cassette exon. Mechanistically, RPS24L and RPS24S are induced and repressed, respectively, by distinct pathways in hypoxia: RPS24L is induced in an autophagy‐dependent manner, while RPS24S is reduced by mTORC1 repression in a hypoxia‐inducible factor‐dependent manner. RPS24L produces a more stable protein isoform that aids in hypoxic cell survival and growth, which could be exploited by cancer cells in the tumor microenvironment.

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Short-term hypoxia triggers ROS and SAFB mediated nuclear matrix and mRNA splicing remodeling

Cited by 7 publications

References 61 publications

Insight into the Structural Basis for Dual Nucleic Acid—Recognition by the Scaffold Attachment Factor B2 Protein

Insight into the Structural Basis for Dual Nucleic Acid—Recognition by the Scaffold Attachment Factor B2 Protein

Insight into the structural basis for dual nucleic acid - recognition by the Scaffold Attachment Factor B2 protein

Autophagy‐dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival

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